Utilizing Genomic Profiling to Refine Risk Stratification for Smoldering and Newly Diagnosed Multiple Myeloma
Key Clinical Takeaways
- Population and Focus: At the 2025 LL&M Congress (New York, NY), Mark Bustoros, MD, Weill Cornell Medicine, reviewed how genomic profiling refines risk assessment and therapeutic strategies across the MM disease continuum.
- Findings: Genomic alterations enhance clinical risk models for smoldering MM, improving prediction of progression risk. Key high-risk abnormalities now include del(17p), t(4;14), del(1p), and 1q gain, which define molecularly high-risk MM requiring intensified therapy.
- Clinical Relevance: Next-generation sequencing (NGS) enables real-time detection of mutations associated with CAR T-cell and bispecific therapy resistance, guiding personalized management and supporting adaptive treatment strategies in relapsed/refractory MM.
At the 2025 Lymphoma, Leukemia & Myeloma (LL&M) Congress in New York, New York, Mark Bustoros, MD, Weill Cornell Medicine, New York, New York, highlighted recent advances in genomics that refine risk stratification and treatment strategies across the multiple myeloma (MM) spectrum.
He reviewed emerging insights into genomic mechanisms of resistance to CAR T-cell and bispecific therapies, emphasizing the role of next-generation sequencing in guiding clinical decision-making.
Transcript:
My name is Mark Bustoros. I'm an assistant professor at Weill Cornell Medicine and at the myeloma program at the cancer center.
Today, we discussed in the session about advances and updates in genomics and how they help us understand risk of progression in patients with smoldering myeloma, but also in newly diagnosed patients and mechanisms of resistance to therapy in relapsed/refractory patients.
We presented data about the updates in how genomics and genetic alterations, in addition to the clinical models, help to refine these models and get a better risk assessment of patients who are diagnosed with smoldering multiple myeloma and the risk of progression. We have shown that multiple groups, including ours, illustrated that actually genomic abnormalities in smoldering multiple myeloma improved the risk stratification and precision of the clinical models that are currently used in the clinic.
Then we talked about the updates in identifying high-risk multiple myeloma patients molecularly, and this was the fruit of the first Imagenomics meeting in Spain 3 years ago that we participated at, and we also participated in the cohorts that generated the data where we know now that multiple, like genetic abnormalities, like 17p deletion, 4;14 translocation, 1p deletion or 1q gain, are now defined as high risk molecular abnormalities, and patients who have these abnormalities in their tumor cells are considered high risk multiple myeloma patients and require more aggressive therapy.
We talked the last about mechanisms of resistance and also how genomics helped us understand with now CAR T therapy and bispecific therapies, that mutations and proteins that are targeted by these agents lead to resistance and relapse. Then ,we talked about how this information and how this knowledge actually could be translated in the clinic, and what are the next generation sequencing panels that could be used in the clinic to understand and get real time information about these abnormalities, and how we can modify our management within multiple myeloma patients according to that.
Source:
Bustoros M. Myeloma Genomics: Real-Time Precision Medicine in the Clinic. Presented at Lymphoma, Leukemia & Myeloma Congress; October 14-17, 2025. New York, NY.
